Protected 3,-5-dihydroxy-2,2-dimethyl-valeronitriles for the synthesis of epothilones and epothilone derivatives and process for the production

ABSTRACT

The invention relates to 3,5-dihydroxy-2,2-dimethyl-valeronitriles for the synthesis of epothilones and epothilone derivatives and process for the production of these new intermediate products in the synthesis and the use for the production of epothilones or epothilone derivatives.

[0001] This application claims the benefit of the filing date of U.S.Provisional Application Serial No. 60/313,016 filed Aug. 20, 2001.

[0002] The invention relates to the subject that is characterized in theclaims, i.e., new intermediate products and process for their productionand the use. The process for the production of new intermediate productsstarts from economical starting materials, yields the intermediateproducts in high enantiomer purities, in high chemical purity, in goodyields and allows the industrial-scale production.

[0003] The invention is used in the synthesis of component A fromnatural and synthetically modified epothilones or derivatives.Epothilones are 16-membered macrolide rings that were isolated from thecultures of Myxobacterium Sorangium Cellosum and are representatives ofa class of promising anti-tumor agents that were tested and found to beeffective against a number of cancer lines. A survey of the syntheseshas been described by J. Mulzer et al. in J. Org. Chem. 2000, 657456-7467.

[0004] In the literature, in addition to the natural epothilones, anumber of synthetic epothilone derivatives are described that vary forthe most part within radicals M and T. In most cases, M stands for aheterocyclic radical here. Most syntheses of the natural epothilones andthe synthetic epothilone derivatives use the A-component fragment, whichrepresent carbon atoms C₅-C₁₀ in the macrolide. Within this component A(see below), C₁ is the C₅ in the macrolide and C₆ is the C₁₀ in themacrolide, etc.

[0005] In this connection, T stands for a C1-C4 alkyl or alkenylradical, and Sg1 and Sg2 stand for the protective groups that arefamiliar to one skilled in the art, such as, e.g., the TBDMS group.

[0006] A possible production of the A-component is described in, forexample, WO00/58254. A synthesis of β-keto esters, which can beconverted in multistage sequences into component A, is disclosedtherein. The chirality is introduced by an asymmetric hydrogenation of aβ-keto ester according to Noyori:

[0007] In this connection, the conversion of the ester group into aketone can only be done by means of a multistage sequence. In this case,after a protection of the 1- and 3-hydroxy group, the ester group (C-5atom) is reduced to form alcohol, the oxidation to aldehyde is carriedout, the Grignard addition of an alkyl radical with an alkylmagnesium oralkyllithium compound yields a secondary alcohol, which then isoxidized. To get from the ester to the ketone, a total of 8 steps arenecessary. The direct reaction of an ester is not selective, since theintermediately produced product is further reacted. The followingdiagram shows the entire synthesis pathway:

[0008] A method for creating component A is described by B. Paniker etal. in Tetrahedron 2000, 56, 78-59-7868. It is described there that thealdol reaction with a chiral component yields a less selective reaction.By the round-about way of an N-methylthioacetyl-oxazolidinone, thesynthesis of the chiral C3 atom in a multistage sequence with improveddiastereoselectivity by means of boron enolate is described. To achieveusable diastereoselectivities, a methylthio substitution is necessary;the thio ether is cleaved off after the aldol reaction.

[0009] Further, a sequence can be found in the prior art (R. E. Taylor,Y. Chen, Org. Lett. (2001), 3(14), 2221-2224) in which a phenyl ester isused for the Grignard reaction. The yield that is achieved in this caseis indicated with 77%. In the example that is described by A. Fürstnerin Chem. Comm. 2001, 1057-1059, a 67% yield is achieved. These yields ofthe Grignard reaction from the prior art are significantly less thanthose of this invention.

[0010] In J. Org. Chem. 2000, 65, 7456-7467, an asymmetrical synthesisof a β-keto ester is further described, whereby a variant inasymmetrical form is performed as an aldol reaction. In this method,D-Ts-valine is used as a catalyst, which can be produced from theexpensive amino acid D-valine. This method yields an ee-value of 90%.Another example in this regard is described by R. E. Taylor, Y. Chen,Org. Lett. (2001), 3(14), 2221-2224 as an asymmetrical aldol reaction,in which the yield is 71%.

[0011] Another method for the production of a double TBDMS-protectedA-component-ethyl ketone is finally described by Nicolaou in Chem. Eur.J. 2000, 6, 2783-2800.

[0012] This invention contains the object of being able to produce auniversally usable starting intermediate compound of general formula Ias well as the optically pure antipodes of general formulas Ia, Ib,

[0013] in which R1, R2 can be the same or different and, independentlyof one another, stand for an alcohol protective group that is familiarto one skilled in the art, for example, benzyl, 4-methoxybenzyl,3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl,trityl, or, in the case when R1 and R2 are bridged, stand for a ketalprotective group, such as, e.g.,

[0014] to produce A-component fragments for epothilone total syntheses.

[0015] To this end, compounds of general formula I are reacted asdescribed below:

[0016] The reactions of the compounds of general formula I, as well astheir antipodes Ia, Ib to form ketones AK are carried out withmethyllithium or methyl-Grignard compounds according to the standardprocess that is known to one skilled in the art; the aqueous working-upthen yields the ketone. The subsequent alkylation with an alkyl oralkenyl-halide of formula T-Hal (Hal=Cl, Br, I or tosylate, mesylate,triflate, etc.) with the addition of a base yields the A-componentfragments.

[0017] A can also be directly obtained, however, by the amides ofgeneral formula I being reacted directly with organometallic compounds,such as, e.g., the lithium compound Li-CH2-T and then being worked up inaqueous form.

[0018] As a rule, the above-described reactions run smoothly and producethe A components in high yields.

[0019] There was therefore a need for an industrial-scale process thatallows it to prepare a universally usable intermediate compound for theproduction of the A component in the epothilone total synthesis.

[0020] In addition to the high yields in the conversion into the Acomponents, the relatively easy accessibility of the compounds ofgeneral formula I from relatively inexpensive starting materials can beemphasized. Moreover, the compounds according to the invention arestable in storage in contrast to the esters and ketones that are knownin the literature and can be reacted as needed during a continuoussynthesis campaign. For the most part, the compounds of general formulaI are crystalline solids and can be purified by crystallization. In thisway, high chemical and optical yields (e.e. >98%) can be achieved.

[0021] The object of the invention is achieved by the preparation of thenew compounds of general formulas I, Ia, Ib

[0022] in which R1, R2 can be the same or different, and, independentlyof one another, stand for an alcohol protective group, such as, e.g.,benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP,TBDPS, MEM, MOM, allyl, trityl,

[0023] or in the case when R1 and R2 are bridged, stand for a ketalprotective group, such as, e.g.,

[0024] For the production of the compounds according to the invention, atotal of 4 variants can be indicated:

Variant I (General Access via Aldol Reactions)

[0025] a) In the case where R1 and R2 stand for a ketal protectivegroup, or R1=R2, compounds of general formula I can be produced fromcompounds of formula II, 2,2-dimethyl -3,5-dihydroxy-valero-nitrile

[0026] according to the methods for protective group chemistry that areknown to one skilled in the art; thus, for example, their production andcleavage are described in P. J. Kocienski in “Protecting Groups,” GeorgThieme Verlag Stuttgart, New York, 1994, as well as in Houben Weyl, 4thEdition, Volume VI/1, p. 737, Thieme Stuttgart 1984.

[0027] b) In the case that R1 and R2 do not represent anyketal-protective group but nevertheless can be the same or different,the production of the compounds of general formula I can be carried outdirectly from the compounds of general formula III, by protective groupR2 being introduced according to methods that are known in theliterature.

[0028] Compounds of general formula II can be produced from compounds ofgeneral formula III

[0029] in which R1 stands for a protective group in the above-indicatedmeaning, by cleavage of protective group R1 according to the process,known to one skilled in the art, of the protective group cleavage ofalcohols (P. J. Kocienski in “Protecting Groups,” Georg Thieme VerlagStuttgart, New York 1994 Houben Weyl, 4th Edition Volume VI/1p. 737,Thieme Stuttgart 1984).

[0030] Compounds of general formula III can be produced from compoundsof general formula IV

[0031] by reaction with the compound of formula V,2-methylpropionitrile,

[0032] in which R1 is in the above-indicated meaning, in a way that isknown to one skilled in the art by the techniques of the aldolcondensation.

[0033] The production of compounds of general formula IV are known toone skilled in the art, however:

[0034] R1=THP in JOC, 1984, 49, 2301-23091

[0035] R1=benzyl in J. Chem. Soc. Perk. Trans 1, 2000, 2429-2454,

[0036] R1=TBDMS in JOC, 2000, 65, 7456-7467

[0037] The compound of formula V, 2-methylpropionitrile, is acommercially available product.

Variant II (Production of Optically Active Intermediate Products ofGeneral Formula Ia)

[0038] For the production of optically active compounds of generalformula Ia

[0039] the procedure is analogous to that described under Variant I.Starting from the optically active intermediate stage of generalformulas IIa and IIIa

[0040] compounds of general formula Ia are produced.

[0041] Compounds of general formula IIa are produced analogously fromthe optically active precursors of general formula IIIa

[0042] Optically active compounds of general formula IIIa are accessibleas follows:

[0043] 1. Separation of the racemic compound of general formula m in thechiral phase (Lit.: G. Roussel, P. Piras, Chirabase, Pure and AppliedChemistry, 1993, 65, 235-244), primarily by SMB technique: A.Seidel-Morgenstem et al., Chromat. A. 1998, 827/2, 175-191.

[0044] 2. By starting from the racemic alcohol of general formula III,esters of general formula VI

[0045]  in which R3 stands for a C1-C6 alkyl group or an allyl, phenylor benzyl group, are produced according to the process of esterificationthat is known to one skilled in the art.

[0046]   And the latter is saponified enantioselectively by enzymatic ormicrobiological methods. The alcohol that is produced is clearlydistinguished in its Rf value from the ester that is used so that thetwo can easily be separated from another, e.g., by columnchromatography.

[0047] 3. By aldol condensation that is mediated with chiral catalysts,by compounds of general formulas IV and V being reacted with use of acatalytic or stoichiometric amount of a chiral aldol catalyst:

[0048]  Literature: See, e.g., J. Org. Chem. 2000, 65, 7456-7467

[0049] 4. By a chiral reduction of the ketone of general formula VII

[0050]  being performed according to methods that are known to oneskilled in the art. Lit.: Noyori et al., J. Am. Chem. Soc. 1987, 109,5850; Noyori et al., J. Am. Chem. Soc. 1988, 110, 629, R. C. Larock in“Comprehensive Organic Transformations,” VCH Publishers New York 1989,ISBN 0-89573-710-8, pages 540-548.

[0051] Compounds of general formula VII, with R1 in the above-indicatedmeaning, can be obtained by reaction of the compound of formula V withcompounds of general formula VIII

[0052] in which Nu stands for a leaving group, such as Cl, Br,imidazole, —OPh, —O—C6H4NO2, —O—C1-C4 alkyl, etc.

[0053] The reaction is carried out in a way that is known to one skilledin the art.

[0054] The production of compounds of general formula VIII is describedin the literature: J. Med. Chem. 1999, 706-721.

[0055] In some cases, it has proven advantageous when compounds ofgeneral formula VII are produced by oxidation from the racemic alcoholsof general formula II according to the methods of oxidation that areknown to one skilled in the art (e.g., Swem oxidation, PDC, PCC, etc.).

[0056] In some cases, it has proven advantageous when a compound offormula V is reacted with propiolactone to form a compound of IX:

[0057] The compound of formula IX can be converted very easily intocompounds of general formula VII by introducing protective groupsaccording to the methods that are known to one skilled in the art (see:P. J. Kocienski in “Protecting Groups,” Georg Thieme Verlag Stuttgart,New York 1994, as well as in Houben Weyl, 4th Edition, Volume VI/1b, p.737, Thieme Stuttgart 1984).

[0058] Starting from compounds of formula IX, however, a compound offormula IIa

[0059] can be obtained by the keto group being reduced chirally withchemical or microbiological methods (e.g., according to: JOC1985, 50,127/J. Chem. Soc., Chem. Commun. 1987, 1368).

Variant III

[0060] Compounds of general formula Ia

[0061] can also be produced by introducing protective groups accordingto methods that are known in the literature for introducing alcoholprotective groups from the compounds of general formula X

[0062] (see literature cited above for introducing protective groups).

[0063] Compounds of general formula X can be produced from compounds ofgeneral formula XI

[0064] in which R4 stands for a methyl, ethyl or benzyl group, by esterreduction according to methods that are known to one skilled in the art.

[0065] Compounds of general formula XI can be produced from compounds ofgeneral formula XII

[0066] in which R4 stands for a C1-C6 alkyl, methyl, ethyl, tert-butyl,phenyl or benzyl group, by introducing protective group R2 according tomethods that are known to one skilled in the art (see above).

[0067] Compounds of general formula XII can be obtained from β-ketoesters of general formula XIII

[0068] by methods of chiral reduction (chemical or enzymatic).

[0069] Compounds of general formula XIII are obtained by reaction ofcompounds of general formula XIV with a compound of formula V

[0070] Compounds of general formula XIV are known in the literature orcan be obtained from the reaction of compounds of general formulas XIIIaand XIIIb.

[0071] Here, Nu is in the meaning of the leaving group that is alreadymentioned above, and Q stands for a hydrogen atom or a COOH group. If Qis a hydrogen atom, XIIIa is deprotonated with an organic base, such as,e.g., LDA and then is reacted with the activated acid derivativeaccording to the method that is familiar to one skilled in the art.

[0072] In the case of Q being equal to COOH, the procedure is performedwith the methods of the malonic acid-semi-ester condensation, asdescribed in, e.g., J. Am. Chem. Soc. 1999, 121, 7050-7062, Synth.Commun. 1997, 27, 3227-3234.

[0073] Compounds of general formula XIIIa are commercially available(e.g., Aldrich).

[0074] Compounds of general formula XIIIb are produced as described inR. C. Larock in “Comprehensive Organic Transformations,” VCH PublishersNew York 1989, ISBN 0-89573-710-8, pages 963-964.

[0075] In some cases, it has proven advantageous to run the diols ofgeneral formula IIa

[0076] directly through the compounds of general formula XII

[0077] by reduction of the ester group according to the above-mentionedprocess.

[0078] The production of racemic diol of general formula II can also useas starting compounds β-keto esters of general formula XIII

[0079] according to the commonly used methods for reduction of estersand ketones.

Variant IV

[0080] In some cases, for the production of optically active diols ofgeneral formula IIa, it has proven advantageous to undertake achromatographic separation or crystallization of the diastereomericketals of general formulas XIVa and XIVb

[0081] in which A is taken for the radical of an optically activeketone, such as, e.g., (−) menthone, (−) camphor, etc., and then theketal group is cleaved off according to the methods of protective groupchemistry that are known to one skilled in the art.

[0082] The production of diastereomeric 1,3 diol-ketals of generalformulas XIVa and XIVb is carried out from the racemic diol of generalformula II by reaction with chiral ketones according to processes thatare known in the literature. Lit.: T. Harada et al., J. Org. Chem. 1992,57, 1412-1421.

[0083] Of course, the corresponding enantiomer compounds of generalformula Ib

[0084] can also be produced with use of mirror-image catalysts or otherenzyme systems.

[0085] There is also the possibility of obtaining the correspondingenantiomers in intermediate stages of general formula IIIb

[0086] by inversion of the hydroxyl group according to Mitsunobu (Lit.:Synthesis 1981, 1-28).

[0087] Of protective groups R1 and R2 that are used in the synthesis,the benzyl group and the TBDMS group are preferred. In the case that R1,R2 stands for a ketal protective group, especially —(C(CH3)2)— ispreferred.

[0088] Of the different production variants here, the following partialsequences are especially preferred for the creation of achiralprecursors:

[0089] 1. Production of the compound of general formula VII from theintermediate stages of general formulas V and VIII

R1=benzyl, Nu=Cl

[0090] 2. Production of the compound of general formula XIII fromcompounds of general formulas V and XIV

R4=ethyl, Nu=Cl

[0091] 3. Production of the compounds of general formula VII by aldolcondensation and subsequent oxidation

R1=benzyl, Nu=Cl

[0092] 4. Production of the compounds of general formula IX (withY=dimethylamino)

[0093] For the production of chiral precursors, especially the partialsteps that are indicated below are preferred:

[0094] 1. Chiral aldol condensation with a chiral catalyst

[0095] 2. Enantioselective saponification of an acetate with the aid ofan enzyme

[0096]  chromatographic separation

[0097] 3. Chiral reduction of a β-keto nitrile (Noyori type)

[0098] 4. Chiral reduction of the β-keto ester with subsequent reduction

[0099] The production of the compounds according to the invention iscarried out preferably in the sequences that are described below:

[0100] 1. Production of acetone ketals

[0101] 2 Production of the Di-TBDMS-protected compound

[0102] The production of the compounds and process according to theinvention is to be explained in more detail in the embodiments below.

[0103] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The following preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

[0104] In the foregoing and in the following examples, all temperaturesare set forth uncorrected in degrees Celsius and, all parts andpercentages are by weight, unless otherwise indicated.

EXAMPLE 1 EXAMPLE1a5-Benzyloxy-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile

[0105] 5.47 g (79.17 mmol) of isobutyric acid nitrile is added in dropsat −65° C. to an LDA solution (produced from 33.64 g (79.17 mmol) ofn-butyllithium 15% in hexane, (1.6 M) and 80.1 g (79.17 mmol) ofdiisopropylamine), and it is stirred for 20 minutes at −65° C. Then, asolution that consists of 10 g (60.9 mmol) of3-benzyloxy-1-propanaldehyde in 20 ml of THF is added in drops (over 60minutes). The temperature is kept at −65° C.! Then, it is stirred forone more hour. It is now heated to −20° C., a solution that consists of20% sulfuric acid is added in drops, and the temperature is allowed toreach +10° C. Then, 50 ml of MTB-ether is added, and then the organicphase is separated. The organic phase is washed with water and then withsaturated sodium bicarbonate. Finally, it is washed once more with waterand then evaporated to the dry state in a vacuum.

[0106] Yield: 13.1 g (92% of theory) of a colorless oil. Elementaryanalysis: C H N Cld. 72.07 8.21 6.00 Fnd. 72.34 8.43 5.85

EXAMPLE 1b 5-Benzyloxy-2,2-dimethyl-3(R,S)-acetoxy-pentane-nitrile

[0107] 14.56 g (42.64 mmol) of acetic acid anhydride is added at 0° C.to a solution that consists of 25.6 g (109.7 mmol) of5-benzyloxy-2,2-dimethyl-3-hydroxy-pentane-nitrile of the title compoundof Example 1a, 14.43 g (142.64 mmol) of triethylamine and 200 mg of4-dimethylaminopyridine (DMAP), dissolved in 128 ml of MTB-ether, and itis stirred for 5 hours at room temperature. The reaction mixture ispoured onto 21 of ice water and extracted twice with 300 ml each ofMTB-ether. The combined MTB-phases are washed once with 300 ml of 5%hydrochloric acid and then with water. It is evaporated to the dry statein a vacuum.

[0108] Yield: 28.82 g (95% of theory) of a colorless oil. Elementaryanalysis: C H N Cld. 69.79 7.69 5.09 Fnd. 69.51 8.01 4.83

EXAMPLE 1c 5-Benzyloxy-2,2-dimethyl-3 (S)-hydroxy-pentane-nitrile

[0109] 10 g (36.31 mmol) of5-benzyloxy-2,2-dimethyl-3(R,S)-acetoxy-pentane-nitrile of the titlecompound of Example 1b is added to a buffer solution, produced from 0.88g of potassium dihydrogen phosphate and 1.82 g of disodium hydrogenphosphate in 250 ml of water. Then, 5 g of the enzyme lipase AYS “Amano”(related to Amano) is added, and it is stirred for 24 hours at 40° C.The pH is brought to 7 by adding 2.062 g of disodium hydrogen phosphate,and then stirring is continued with HPLC monitoring at intervals of 12hours with HPLC monitoring until the peak of the R-acetate is less than1% of the surface area. Working-up: It is extracted twice with 200 ml ofethyl acetate. The organic phases are combined and evaporated to the drystate in a vacuum. The purification is carried out by chromatography onsilica gel (hexane/ethyl acetate gradient). With the first fraction, 4.2g (45% of theory) of5-benzyloxy-2,2-dimethyl-3(R)-hydroxy-pentane-nitrile is obtained, andwith the second fraction, 4.8 g (48% of theory) of5-benzyloxy-2,2-dimethyl-3(S)-acetoxy-pentane-nitrile is obtained.

[0110] 4.8 g (17.5 mmol) of5-benzyloxy-2,2-dimethyl-3(S)-acetoxy-pentane-nitrile from the secondfraction is dissolved in 50 ml of methanol and mixed with 1.4 g (35mmol) of NaOH. It is stirred for 3 hours at 250C, added to 200 ml ofwater, extracted with 2×200 ml of MTB ether, dried on sodium sulfate andconcentrated by evaporation.

[0111] Yield: 4 g (47% of theory) of5-benzyloxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile as a colorlessoil. Elementary analysis: C H N Cld. 72.07 8.21 6.00 Fnd. 71.85 8.415.87

EXAMPLE 1d 5-Hydroxy-2,2-dimethyl-3 (S)-hydroxy-pentane-nitrile

[0112] 16 g of Pearlman's catalyst (Pd(OH)₂ on carbon, 20%) is added to11.13 g (47.70 mmol) of5-benzyloxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile of the titlecompound of Example 1c, dissolved in 110 ml of tetrahydrofuran. It isnow hydrogenated for 7.5 hours at 10 bar and at room temperature.Catalyst is filtered out, and the filtrate is evaporated to the drystate in a vacuum.

[0113] Yield: 6.73 g (98% of theory) of a colorless, viscous oil.Elementary analysis: C H N Cld. 58.72 9.15 9.78 Fnd. 58.64 9.23 9.69

EXAMPLE 1e 3(S)-(3,5) Acetone dimethylketal-2,2-dimethyl-pentane-nitrile

[0114] 6.73 g (47 mmol) of5-hydroxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile of the titlecompound of Example 1d is dissolved in 27 ml of acetone dimethylketal,and 546 mg of camphor-10-sulfonic acid is added. It is heated for 15hours to 50° C. It is evaporated to the dry state in a vacuum. Theresidue is taken up in 200 ml of methylene chloride and washed withsaturated sodium bicarbonate solution and then with saturated sodiumchloride solution. The organic phase is dried on sodium sulfate andevaporated to the dry state in a vacuum. The oil that is obtainedcrystallizes while standing.

[0115] Yield: 5.55 g, (77% of theory) of colorless crystalline solid.Elementary analysis: C H N Cld. 65.54 9.35 7.64 Fnd. 65.38 9.29 7.58

EXAMPLE 23(S)-3,5-Di-tert-butyldimethylsilyloxy-2,2-dimethyl-pentane-nitrile

[0116] 7.13 g (104.75 mmol) of imidazole and 7.9 g (52.37 nm/mol) oftert-butyldimethylsilyl chloride are added to a solution that consistsof 3 g (20.95 mmol) of5-hydroxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile of the titlecompound of Example 1d, in 20 ml of dimethylformamide, and it is stirredfor 16 hours at room temperature. The solution is poured onto 200 ml ofwater and extracted twice with 50 ml of cyclohexane each. The organicphases are combined and evaporated to the dry state in a vacuum. Theresidue is purified by flash chromatography on silica gel (hexane/MTBether).

[0117] Yield: 7.39 g, (95% of theory) of a colorless, viscous oil.Elementary analysis: C H N Cld. 61.39 11.12 3.77 Fnd. 62.00 11.30 3.80

EXAMPLE 33(S)-3,5-Cyclohexanone-dimethylketal-2,2-dimethyl-pentane-nitrile

[0118] 10 mg of p-toluenesulfonic acid is added to a solution thatconsists of 3 g (20.95 mmol) of5-hydroxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile of the titlecompound of Example 1f in 30.21 g (0.2095 mol) ofcyclohexanone-dimethylketal, and it is stirred for 6 hours at 100° C.The solution is poured onto 200 ml of water and extracted twice with 50ml of ethyl acetate each. The organic phases are combined and evaporatedto the dry state in a vacuum. The residue is purified by flashchromatography on silica gel (hexane/MTB-ether).

[0119] Yield: 4.21 g (90% of theory) of a colorless, viscous oil.Elementary analysis: C H N Cld. 69.92 9.48 6.27 Fnd. 69.81 9.62 6.15

EXAMPLE 43(S)-3,5-Benzaldehyde-dimethylacetal-2,2-dimethyl-pentane-nitrile

[0120] 31.9 g (0.2095 mol) of benzaldehyde-dimethylacetal and 50 mg ofp-toluenesulfonic acid are added to a solution that consists of 3 g(20.95 mmol) of 5-hydroxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile ofthe title compound of Example 1f, in 20 ml of dimethylformamide, and itis stirred for 16 hours at 100° C. The solution is poured onto 200 ml ofwater and extracted twice with 50 ml of ethyl acetate each. The organicphases are combined and evaporated to the dry state in a vacuum. Theresidue is purified by flash chromatography on silica gel(hexane/MTB-ether).

[0121] Yield: 4.26 g (88% of theory) of a colorless, viscous oil.Elementary analysis: C H N Cld. 69.92 9.48 6.27 Fnd. 69.81 9.62 6.15

EXAMPLE 5 3(S)-3,5-Dichlorodiphenylsilane-2,2-dimethyl-pentane-nitrile

[0122] 3.14 g (46.09 mmol) of imidazole and 5.83 g (23.05 mmol) ofdichlorodiphenylsilane are added to a solution that consists of 3 g(20.95 mmol) of 5-hydroxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile ofthe title compound of Example 1f, in 20 ml of dimethylformamide, and itis stirred for 16 hours at room temperature. The solution is poured onto200 ml of water and extracted twice with 50 ml of methylene chlorideeach. The organic phases are combined and evaporated to the dry state ina vacuum. The residue is purified by flash chromatography on silica gel(hexane/MTB-ether).

[0123] Yield: 5.76 g (85% of theory) of a colorless, viscous oil.Elementary analysis: C H N Cld. 70.55 6.54 4.33 Fnd. 70.41 6.71 4.25

EXAMPLE 6a5-tert-Butyldimethylsilyl-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile

[0124] 4.62 g (66.99 mmol) of isobutyric acid nitrile is added in dropsat −65° C. to an LDA solution (produced from 28.6 g (66.99 mmol) ofn-butyllithium 15% (1.6 M) and 6.82 g, 66.99 mmol, of diisopropylamine),and it is stirred for 20 minutes at −65° C. Then, a solution thatconsists of 11.47 g (60.9 mmol) of5-tert-butyldimethylsilyl-1-propanaldehyde in 20 ml of THF is added indrops (over 60 minutes). The temperature is held at −65° C.! Then, it isstirred for one more hour. It is now heated to −20° C., and a solutionof 130 ml of 1N hydrochloric acid is added in drops, and the temperatureis allowed to come to +10° C. Then, 50 ml of MTB-ether is added, andthen the organic phase is separated. The organic phase is washed withwater and then saturated sodium bicarbonate solution. Finally, it iswashed once more with water and then evaporated to the dry state in avacuum.

[0125] Yield: 13.65 g (87% of theory) Elementary analysis: C H N Cld.60.65 10.57 5.44 Fnd. 60.48 10.65 5.37

EXAMPLE 6b 5-Hydroxy-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile

[0126] 12.18 g (46.61 mmol) of tetrabutylammonium fluoride hydrate isadded to a solution that consists of 3 g (11.65 mmol) of5-tert-butyldimethylsilyl-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile ofthe title compound of Example 6a, dissolved in 40 ml of tetrahydrofuran,and it is stirred for 16 hours at room temperature. Then, it isevaporated to the dry state in a vacuum. The residue is purified byRP-18 chromatography (mobile solvent: acetonitrile/water gradient).

[0127] Yield: 1.41 g (85% of theory) of a colorless, viscous oil.Elementary analysis: C H N Cld. 58.72 9.15 9.78 Fnd. 58.51 9.23 9.64

EXAMPLE 6c (−)-Camphor Ketal 3(S)-(3,5)Camphordimethylketal-2,2-dimethyl-pentane-nitrile

[0128] 6.73 g (47 mmol of5-hydroxy-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile of the titlecompound of Example 6b,dissolved in 27 ml of methylene chloride, isadded with 93 g of (1S)-(−) -camphor ketal (produced from(1S)-(−)-camphor, methanol and p-toluenesulfonic acid), and 546 mg ofcamphor-10-sulfonic acid. It is refluxed for 15 hours. The batch isdiluted in 200 ml of methylene chloride and washed with saturated sodiumbicarbonate solution, then with saturated sodium chloride solution. Theorganic phase is dried on sodium sulfate and evaporated to the dry statein a vacuum. The residue is chromatographed on a chiral phase (mobilesolvent: acetonitrile/water gradient). The oil that is obtainedcrystallizes while standing.

[0129] Yield: 10 g, (77% of theory) of a colorless, crystalline solid.Elementary analysis: C H N Cld. 73.61 9.81 5.05 Fnd. 73.40 9.79 5.00

EXAMPLE 6d 5-Hydroxy-2,2-dimethyl-3 (S)-hydroxy-pentane-nitrile Cleavageof the Camphor Ketal

[0130] 13 g (47 mmol) of 3(S)-(3,5)camphordimethylketal-2,2-dimethyl-pentane-nitrile of the compound ofExample 6c is dissolved in 40 ml of tetrahydrofuran, 12.18 g (46.61mmol) of tetrabutylammonium fluoride hydrate is added, and it is stirredfor 16 hours at room temperature, then it is evaporated to the dry statein a vacuum. The residue is purified by RP-18 chromatography (mobilesolvent: acetonitrile/water gradient).

[0131] Yield: 5.72 g (85% of theory) of a colorless, viscous oil.Elementary analysis: C H N Cld. 58.72 9.15 9.78 Fnd. 58.60 9.00 9.60

EXAMPLE 7 5-Benzyloxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile and5-Benzyloxy-2,2-dimethyl-3(R)-hydroxy-pentane-nitrile

[0132] The title compound of Example 1a,5-benzyloxy-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile, ischromatographed on a chiral phase (10 g on Chiralpak AD 20 μ/eluant:hexane/ethanol 98:2, wavelength: 208 nm).

[0133] The following are obtained:

[0134] R-Isomer, yield: 3.8 g (38% of theory) of a colorless, viscousoil. Elementary analysis: C H N Cld. 58.72 9.15 9.78 Fnd. 58.59 9.319.71

[0135] S-Isomer, yield: 4.1 g (41% of theory) of a colorless, viscousoil. Elementary analysis: C H N Cld. 58.72 9.15 9.78 Fnd. 58.61 9.279.69

EXAMPLE 8a5-tert-Butyldimethylsilyl-2,2-dimethyl-3(R,S)acetoxy-pentane-nitrile

[0136] 14.43 g (142.64 mmol) of triethylamine and 200 mg of4-dimethylaminopyridine (DMAP), dissolved in 128 ml of MTB-ether, and,at 0° C., 14.56 g (142.64 mmol) of acetic acid anhydride are added to28.24 g (109.7 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile, the title compound of Example 6a, and it isstirred for 5 hours at room temperature. It is poured onto 21 of icewater and extracted twice with 300 ml each of MTB-ether. The combinedMTB-phases are washed once with 300 ml of 5% hydrochloric acid and thenwith water. It is evaporated to the dry state in a vacuum. The residueis purified by flash chromatography on silica gel (hexane/MTB-ether).

[0137] Yield: 31.21 g (95% of theory) of a colorless oil. Elementaryanalysis: C H N Cld. 60.16 9.76 4.68 Fnd. 60.02 9.85 4.59

EXAMPLE 8b5-tert-Butyldimethylsilyl-2,2-dimethyl-3(S)hydroxy-pentane-nitrile

[0138] 10 g (33.39 mmol) of5-tert-butyldimethylsilyl-2,2-dimethyl-3(R,S)-acetoxy-pentane-nitrile ofthe title compound of Example 8a is added to a buffer solution, producedfrom 0.88 g of potassium dihydrogen phosphate and 1.82 g of disodiumhydrogen phosphate in 250 ml of water. Then, 5 g of the enzyme lipaseAYS “Amano” (related to Amano) is added, and it is stirred for 42.5hours at room temperature. The pH is brought to 7 by adding 2.062 g ofsodium hydrogen phosphate, and then stirring is continued for 44.5hours. Working-up: It is extracted 3 times with 200 ml of ethyl acetate.The organic phases are combined and evaporated to the dry state in avacuum. The purification is carried out by chromatography on silica gel(hexane/ethyl acetate gradient).

[0139] 3.8 g (45%) of5-tert-butyldimethylsilyl-2,2-dimethyl-3(R)-hydroxy-pentane-nitrile and4.8 g (48%) of5-tert-butyldimethylsilyl-2,2-dimethyl-3(S)-acetoxy-pentane-nitrile areobtained.

[0140] 4.8 g (16 mmol) of5-tert-butyldimethylsilyl-2,2-dimethyl-3(S)-acetoxy-pentane-nitrile isdissolved in 50 ml of ethanol and mixed with 1.28 g of NaOH (32 mmol).It is stirred for 3 hours at 25° C., added to 200 ml of water, extractedwith 2×200 ml of MTB ether, dried on sodium sulfate and concentrated byevaporation.

[0141] Yield: 3.43 g (40% of theory) Elementary analysis: C H N Cld.60.65 10.57 5.44 Fnd. 60.54 10.64 5.37

EXAMPLE 8c3(S)-3,5-Di-tert-butyldimethylsilyloxy-2,2-dimethyl-pentane-nitrile

[0142] 2.37 g (34.95 mmol) of imidazole and 2.63 g (17.47 mmol) oftert-butyldimethylsilyl chloride are added to a solution that consistsof 3 g (11.65 mmol) of5-tert-butyldimethylsilyl-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile ofthe title compound of Example 8b, dissolved in 10 ml ofdimethylformamide, and it is stirred for 16 hours at room temperature.The solution is poured onto 100 ml of water and extracted twice with 50ml of MTB-ether each. The organic phases are combined and evaporated tothe dry state in a vacuum. The residue is purified by flashchromatography on silica gel (hexane/MTB-ether).

[0143] Yield: 4.11 g (95% of theory) of a colorless, viscous oil.Elementary analysis: C H N Cld. 61.39 11.12 3.77 Fnd. 61.31 11.25 3.64

EXAMPLE 9 5-Hydroxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile

[0144] 12.18 g (46.61 mmol) of tetrabutylammonium fluoride hydrate isadded to a solution that consists of 3 g (11.65 mmol) of5-tert-butyldimethylsilyl-2,2-dimethyl-3(S)hydroxy-pentane-nitrile ofthe title compound of Example 8b, dissolved in 40 ml of tetrahydrofuran,and it is stirred for 16 hours at room temperature. Then, it isevaporated to the dry state in a vacuum. The residue is purified byRP-18 chromatography (mobile solvent: acetonitrile/water gradient).

[0145] Yield: 1.41 g (85% of theory) of a colorless, viscous oil.Elementary analysis: C H N Cld. 58.72 9.15 9.78 Fnd. 58.61 9.23 9.69

EXAMPLE 10a 5-Benzyloxy-2,2-dimethyl-3-keto-pentane-nitrile

[0146] 5.47 g (79.17 mmol) of isobutyric acid nitrile is added in dropsat −65° C. to an LDA solution (produced from 33.64 g (79.17 mmol) ofn-butyllithium (15%, 1.6M) and 80.1 g (79.17 mmol) of diisopropylamine),and it is stirred for 20 minutes at −65° C. Then, a solution thatconsists of 14.29 g (71.97 mmol) of 3-benzyloxy-1-propionic acidchloride in 20 ml of THF is added in drops (60 minutes). The temperatureis held at −65° C.! Then, stirring is continued for one hour. It isheated to −20° C., and a solution that consists of 20% sulfuric acid isadded in drops, and the temperature is allowed to reach +10° C. Then, 50ml of MTB-ether is added, and then the organic phase is separated. Theorganic phase is washed with water and then with saturated sodiumbicarbonate solution. Finally, it is washed once more with water andthen evaporated to the dry state in a vacuum. The residue is purified byflash chromatography on silica gel (hexane/MTB-ether).

[0147] Yield: 14.15 g (85% of theory) of a colorless, viscous oil.Elementary analysis: C H N O Cld. 72.70 7.41 6.06 13.83 Fnd. 72.54 7.585.87

EXAMPLE 10b 5-Hydroxy-2,2-dimethyl-3-keto-pentane-nitrile

[0148] 3 g of Pearlman's catalyst (Pd(OH)₂ on carbon, 20%) is added to10 g (43.23 mmol) of 5-benzyloxy-2,2-dimethyl-3-keto-pentane-nitrile ofthe title compound of Example 10a, dissolved in 100 ml of methanol. Itis now hydrogenated for 7.5 hours at 10 bar and at room temperature.Catalyst is filtered out, and the filtrate is evaporated to the drystate in a vacuum.

[0149] Yield: 5.98 g (98% of theory) of a colorless, viscous oil.Elementary analysis: C H N Cld. 59.56 7.85 9.92 Fnd. 59.47 7.94 9.85

EXAMPLE 10c 3(S),5-Dihydroxy-2,2-dimethyl-pentane-nitrile

[0150] 5 g (35.41 mmol) of 5-hydroxy-2,2-dimethyl-3-keto-pentane-nitrileof the title compound of Example 10b is hydrogenated with a catalyst(produced from 233 mg of RuCl₂(Ph)₂ and 626 mg of R-BINAP according toR. Selke, Angew. Chem. [Applied Chem.] 1998, 110, pp. 1927-1930) (at 40°C. and 100 bar). Catalyst is filtered out, and the filtrate isevaporated to the dry state in a vacuum.

[0151] Yield: 4.96 g (98% of theory) of a colorless, viscous oil.Elementary analysis: C H N Cld. 58.72 9.15 9.78 Fnd. 58.65 9.26 9.71

EXAMPLE 11 S-3-(2,2-Dimethyl-[1,3]dioxan-4-yl)-3-methyl-butan-2-one

[0152] 35.6 ml of methyllithium-lithium bromide complex (1.5 M indiethyl ether) is added in drops at −20° C. to 3.26 g (17.79 mmol) ofthe title compound of Example 1e, 3(S)-(3,5)-acetonedimethylketal-2,2-dimethyl-pentane-nitrile, dissolved in 5 ml of diethylether. Then, it is stirred for 30 minutes at −20° C. and then heated toroom temperature. It is stirred overnight at room temperature. 10 ml ofsaturated ammonium chloride solution is added, and it is stirred for 6hours at room temperature. The organic phase is separated and washedtwice with water. The organic phase is evaporated to the dry state in avacuum. The purification is carried out by chromatography on silica gel(hexane/ethyl acetate gradient).

[0153] Yield: 2.77 g (78% of theory) of an oil. Elementary analysis: C HCld. 65.97 10.07 Fnd. 65.84 10.19

EXAMPLE 12S-1,3-Bis-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentan-5-one

[0154] 40.35 ml of lithium ethylate (1 M solution in THF) is added indrops at −20° C. to 5 g (13.45 mmol) of the title compound of Example 2,3(S)-3,5-di-tert-butyldimethylsilyloxy-2,2-dimethyl-pentane-nitrile,dissolved in 5 ml of diethyl ether. Then, it is stirred for 30 minutesat −20° C., and then heated to room temperature. It is stirred overnightat room temperature. 10 ml of saturated ammonium chloride solution isadded, and it is stirred for 6 hours at room temperature. The organicphase is separated and washed twice with water. The organic phase isevaporated to the dry state in a vacuum. The purification is carried outby chromatography on silica gel (hexane/ethyl acetate gradient).

[0155] Yield: 4.06 g (75% of theory) of an oil Elementary analysis: C HCld. 62.63 11.51 Fnd. 62.51 11.64

EXAMPLE 13 S-2-(2,2-Dimethyl-[1,3]dioxan-4-yl)-2-methyl-heptan-3-one

[0156] 34 ml of n-butyllithium, 15% (1.6 M in hexane) is added in dropsat −65° C. [to] 3.26 g (17.79 mmol) of the title compound of Example 1e,3(S)-(3,5)-acetone dimethylketal-2,2-dimethyl-pentane-nitrile, dissolvedin 5 ml of THF. Then, it is stirred for five hours at −65° C., and thenit is heated to room temperature. It is stirred overnight at roomtemperature. 10 ml of saturated ammonium chloride solution is added, andit is stirred for 6 hours at room temperature. The organic phase isseparated and washed twice with water. The organic phase is evaporatedto the dry state in a vacuum. The purification is carried out bychromatography on silica gel (hexane/ethyl acetate gradient).

[0157] Yield: 4.13 g (96% of theory) of an oil Elementary analysis: C HCld. 69.38 10.81 Fnd. 69.27 10.96

EXAMPLE 14(4S)-4-(2-Methyl-3-oxo-hept-6-en-2-yl)-2,2-dimethyl-(1,3)dioxane

[0158] 50 ml of 3-butenyllithium solution (produced from4-bromo-1-butenes and lithium wire or tert-butyllithium, according to J.Org. Chem. Vol. 56 No. 21, pp. 6094-6103 (1991) or J. Chem. Soc. PerkinTrans. 1 pp. 2937 (1988)) is added in drops at −90° C. to 3.26 g (17.79mmol) of the title compound of Example 1e, 3(S)-(3,5)-acetonedimethylketal-2,2-dimethyl-pentane-nitrile, dissolved in 5 ml of diethylether. Then, it is stirred for 17 hours at −90° C. and then heated toroom temperature. It is stirred overnight at room temperature for 17hours. 10 ml of saturated ammonium chloride solution is added, and it isstirred for 6 hours at room temperature. The organic phase is separatedand washed twice with water. The organic phase is evaporated to the drystate in a vacuum. The purification is carried out by chromatography onsilica gel (hexane/ethyl acetate gradient).

[0159] Yield: 2.74 g (70% of theory) of a colorless oil. Elementaryanalysis: C H Cld. 69.96 10.06 Fnd. 69.90 10.00

Abbreviations of the Ether Protective Groups that are Used

[0160] TES=Triethylsilyl

[0161] TMS=Trimethylsilyl

[0162] TIP=Triisopropyl

[0163] TBDPS=tert-Butyl-dimethylsilyl

[0164] MEM=Methylethoxymethyl

[0165] MOM=Methyloxymethyl

[0166] THP=Tetrahydropyranyl-(ether)

[0167] The entire disclosures of all applications, patents andpublications, cited herein and of corresponding German Application No.101 38 347.9, filed Aug. 3, 2001, and U.S. Provisional ApplicationSerial No. 60/313,016, filed Aug. 20, 2001 are incorporated by referenceherein.

[0168] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0169] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. Compounds of general formula I

in which R1, R2 can be the same or different and, independently of oneanother, stand for an alcohol protective group, such as, e.g., benzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS,MEM, MOM, allyl, trityl, or, in the case when R1 and R2 are bridged,stand for a ketal protective group, such as, e.g.,


2. Compounds of general formula Ia

in which R1, R2 can be the same or different and, independently of oneanother, stand for an alcohol protective group, such as, e.g., benzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS,MEM, MOM, allyl, trityl, or, in the case when R1 and R2 are bridged,stand for a ketal protective group, such as, e.g.,


3. Compounds of general formula Ib

in which R1, R2 can be the same or different and, independently of oneanother, stand for an alcohol protective group, such as, e.g., benzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS,MEM, MOM, allyl, trityl, or, in the case when R1 and R2 are bridged,stand for a ketal protective group, such as, e.g.,


4. Compounds of formula II, 2,2-Dimethyl-3,5-dihydroxy-valeronitrile andisomers


5. Compounds according to claim 4, characterized in that theconfiguration at the C-atom of the secondary alcohol is S.
 6. Compoundsaccording to claim 4, wherein the configuration at the C-atom of thesecondary alcohol is R.
 7. Compounds of general formula III

in which R1 stands for an alcohol protective group, such as, e.g.,benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP,TBDPS, MEM, MOM, allyl, trityl.
 8. Compounds according to claim 7,wherein the configuration at the C-atom of the secondary alcohol is S.9. Compounds according to claim 7, wherein the configuration at theC-atom of the secondary alcohol is R.
 10. Compounds of general formulaXII

in which R4 stands for a C1-C6 alkyl, methyl, ethyl, tert-butyl, phenylor benzyl group.
 11. Compounds according to claim 10, wherein theconfiguration at the C-atom of the secondary alcohol is R.
 12. Use ofthe compounds according to at least one of claims 1 to 11 for thesynthesis of natural and synthetic epothilones.
 13. Process for theproduction of compounds according to claims 1 to 3, wherein startingfrom the compounds according to claims 4 to 6, the alcohol groups areprotected with protective groups R1 and R2.
 14. Process according toclaim 13, wherein protective groups R1 and R1 represent the acetoneketal and the TBDMS group.
 15. Process for the production of opticallyactive compounds of general formula IIIa,

wherein a racemic ester of general formula VI

 in which R1 stands for an alcohol protective group, such as, e.g.,benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP,TBDPS, MEM, MOM, allyl, trityl, and R3 stands for a C1-C6 alkyl group oran allyl, phenyl or benzyl group, is enantioselectively saponified bymeans of enzymatic saponification.
 16. Process according to claim 15,wherein the enzyme that is used for saponification is lipase amano AY.17. Process for the production of optically active compounds of generalformula IIIa

in which R1 stands for an alcohol protective group, such as, e.g.,benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP,TBDPS, MEM, MOM, allyl, trityl, wherein starting from the compounds offormula VII

 a chiral reduction of the keto group is made.
 18. Process according toclaim 17, wherein the chiral reduction of the keto group is made bycatalytic hydrogenation with a Noyori-type catalyst.
 19. Processaccording to claim 17, wherein the chiral reduction of the keto group ismade by enzymatic reduction.
 20. Process for the production of thecompounds of general formula XIII

in which R4 stands for a C1-C6 alkyl, methyl, ethyl, tert-butyl, phenylor benzyl group, wherein compounds of general formula XIV

 in which R4 stands for a C1-C6 alkyl, methyl, ethyl, tert-butyl, phenylor benzyl group, Nu stands for a leaving group, such as Cl, Br,imidazole, —OPh, —O—C6H4NO2, —O—C1-C4 alkyl, are reacted with a compoundof formula V


21. 3(S)-3,5-Acetone dimethylketal-2,2-dimethyl-pentane-nitrile


22. 3(S)-3,5-Benzaldehyde-dimethylacetal-2,2-dimethyl-pentane-nitrile


23. 3(S)-3,5-Di-tert-butyldimethylsilyloxy-2,2-dimethyl-pentane-nitrile


24. 3,5-Benzaldehyde-dimethylacetal-2,2-dimethyl-pentane-nitrile


25. 3,5-Diphenylsilane-2,2-dimethyl-pentane-nitrile.


26. 5-Hydroxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile.


27. 5-Benzyloxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile.


28. Process for the production of ketones of general formula A

in which R1, R2 can be the same or different and, independently of oneanother, stand for an alcohol protective group, such as, e.g., benzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS,MEM, MOM, allyl, trityl, or, in the case when R1 and R2 are bridged,stand for a ketal protective group, such as, e.g.,

V stands for a C1-C5 alkyl or alkenyl radical, wherein compounds ofgeneral formula Ia

 are reacted with compounds of general formula B M-V (B)  in which Mstands for Li or MgCl, MgBr, or MgI, and then are worked up underaqueous hydrolysis.
 29. Process according to claim 28, wherein compoundsof general formula M-V preferably stand for MeLi, EtLi, propyl-Li, BuLi,CH2═CH—CH2CH2—Li.
 30. Use of the compounds of general formula Iaccording to claim 1 for the production of epothilone or epothilonederivatives.
 31. Use of the compounds of general formula I according toclaim 1 or of general formula Ia according to claim 2 or of generalformula Ib according to claim 3 or of general formula II according toclaim 4 or of general formula III according to claim 7 or of generalformula XII according to claim 10 for the production of epothilones orepothilone derivatives.